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Large-Scale Genetic Study Sheds Light on Lung Cancer

In the largest effort of its kind, scientists have charted the genetic changes involved in the most common form of lung cancer, implicating more than a dozen new genes. The findings should help pave the way for more individualized approaches for detection and treatment.

Lung cancer is the leading cause of cancer deaths both in the
United States and throughout the world. The most frequently diagnosed
form of lung cancer is lung adenocarcinoma, which is extremely
difficult to treat. The vast majority of patients die within
5 years of diagnosis, although earlier detection can prolong
survival.

Like most cancers, lung adenocarcinoma arises from changes
that accumulate in DNA over the course of a person's life. However,
little is known about the precise nature of these DNA changes
and how they disrupt biological pathways to trigger the uncontrolled
cell growth of cancer. To gain a more complete picture, NIH's
National Human Genome Research Institute (NHGRI) launched a multi-institution
collaboration called the Tumor Sequencing Project consortium.

In the consortium's latest study, published in the October
23, 2008, issue of Nature, the researchers analyzed
both tumor samples and noncancerous tissues donated by 188 patients
with lung adenocarcinoma. The scientists sequenced the DNA to
look for mutations in more than 600 genes with known or potential
relationships to cancer.

Prior to the study, fewer than a dozen genes had been implicated
in lung adenocarcinoma. The new study identified 26 genes that
are mutated in a significant number of samples, more than doubling
the number of known genes linked to this deadly disease. Several
of the genes had already been associated with other types of
cancers—including leukemia, colon cancer and cancer of
the retina—suggesting they may contribute to multiple forms
of cancer.

The team also analyzed these genetic glitches to see which
biological pathways are most crucial to lung adenocarcinoma.
More than two-thirds of the 188 tumors studied had at least 1
gene mutation affecting the mitogen-activated protein kinase
(MAPK) pathway, indicating that it plays a pivotal role in lung
cancer. New treatment strategies for some subtypes of lung adenocarcinoma
might target this pathway. Many of the genes also code for cell
receptors coupled to members of the tyrosine kinase family of
enzymes, which are considered prime targets for new cancer therapies.

These findings suggest that certain lung cancer patients might
benefit from chemotherapy drugs currently used to treat other
types of cancer. For example, chemotherapy drugs known to inhibit
the kinase insert domain receptor (KDR), such as sorafenib and
sunitinib, might be tested in the relatively small percentage
of lung adenocarcinoma patients whose tumors have mutations that
activate the KDR gene.

“Our findings underscore the value of systematic, large-scale
studies for exploring cancer,” said Dr. Richard K. Wilson,
Director of the Genome Sequencing Center at Washington University
School of Medicine, St. Louis, and a senior author of the paper. “We
now must move forward to apply this approach to even larger groups
of samples and a wider range of cancers.”